(A) Experimental overview of our B6:MACoV2 model studies, wherein mice were infected via aerosol with Mtb (Day -30) and challenged 30 days later (Day 0) with MACoV2. On post-challenge Days 4, 7 and14 we collected lung tissue for microbiological and immunological assessments. Experimental groups included B6 mice which were not infected with Mtb prior to MACoV2 challenge (MtbNEGMACoV2POS), B6 mice which were infected with Mtb but challenged with sterile saline (MtbPOSMACoV2NEG), and B6 mice which were infected with Mtb prior to CoV2 challenge (MtbPOSMACoV2POS). (B) The percent weight change experienced by each group of B6 mice following MACoV2 challenge, as normalized to the original weight of each mouse. (C-D) Lung viral burdens in MtbNEGMACoV2POS and MtbPOSMACoV2POS mice, as measured by (C) MACoV2 PFU or (D) MACoV2 N protein concentration on the indicated days, as well as (E) lung Mtb CFU burdens at the same timepoints. (F, H) Lung protein levels of (F) IFNγ and (H) IL6, as well as (G, I-K) mRNA levels of (G) IFNγ, (I) IFIT3, (J) IFITM3 and (K) ACE2. This experiment was repeated twice, each with similar results (4 mice/group/timepoint). *, p ≤ 0.05 as determined by either Student’s t-test or ANOVA; §, significant relative to UI protein levels.